TNF is a cytokine which is produced by activated macrophage and other cells and is an important regulator in inflammation and immunity. It is implicated in septic shock--an often fatal condition associated with Gram-negative or Gram-positive bacteremia--as well as in other conditions such as adult respiratory distress syndrome, graft-versus-host disease and auto-immune diseases.
Treatments of these conditions involving the use of antibodies to TNF (anti-TNF antibodies) have been proposed and tested. For example, Beutler et al (Science (1985), 229, 869-871) showed that passive immunisation with a rabbit polyclonal antiserum against TNF protected mice from the lethal effects of Gram-negative endotoxin. Similarly, antibody therapy against TNF has been shown to decrease mortality in mice undergoing graft-versus-host disease (GVHD) and to prevent splenomegaly, and cutaneous and intestinal lesions associated with acute phase GVHD. (Piguet, P. F., et al, J. Exp. Med. 1987; 166: 1280; Shalaby, M. R., et al, Transplantation 1989; 47: 1057).
In addition, patent applications of Celltech Limited disclose the use of anti-TNF antibodies in the amelioration of side effects associated with anti-lymphocyte therapy of graft-rejection (WO89/08460), and with anti-neoplastic chemotherapy (WO89/01950).
Certain xanthine derivatives are also known to be inhibitors of TNF. For example, EP-A-0344586 of Hoechst Aktiengesellschaft discloses xanthine derivatives effective in inhibiting the TNF whose release is induced by certain TNF-releasing substances such as amphoterocin B.
The present inventors have observed that in some experimental models of septic shock a surprising combination effect is produced if an antibody to TNF and a xanthine derivative are used in combination.